While cytotoxic T lymphocytes (CTL) are generally thought to mediate host protective effects by lysis of virally infected cells, such an immune response in the central nervous system (CNS) would be predicted to lead to severe damage to the host if nonrenewable cell populations such as neurons were killed. Therefore, we hypothesize that a noncytolytic immune response leads to viral clearance in the CNS. The long-term objective of this proposal is to determine whether noncytolytic immune responses may contribute to viral clearance, particularly in CNS neurons. Of importance is gaining a clearer understanding of whether noncytolytic virus clearance occurs and is governed by the character of the T cell infiltrate, the accessibility of the immune response to infected cells, or the nature of the infected target cells. In the proposed work, both measles virus and lymphocytic choriomeningitis virus infection of mouse neurons, in vivo and in vitro, will be used to examine the noncytopathic aspect of immune clearance of CNS infection. The mechanism by which CTL may noncytolytically inhibit viral replication in neurons will be characterized, and the necessity of cell-cell contact/antigen recognition for the noncytolytic clearance of viral CNS infections will be determined. Additionally, the impact of CTL-elaborated cytokines on viral replication will be identified. This research may aid in the development of immunotherapy for infectious diseases and in devising immune evasion for gene therapy viral vectors.